Taxanes are one of the important classes of cancer chemotherapeutic agents. Representatives of taxanes include docetaxel, paclitaxel, cabazitaxel, larotaxel, abraxane, paclitaxel pro-drugs, paclitaxel lipid conjugates, paclitaxel polymer conjugates and the like.
Paclitaxel has been approved for clinical use in the treatment of first line and advanced ovarian cancer in the United States and has been approved for treatment of breast cancer, non small cell lung cancer and AIDS related Kaposi's Sarcoma. Paclitaxel is only slightly soluble in water and this has created significant problems in developing suitable injectable and infusion formulations useful for anticancer chemotherapy. Some formulations of paclitaxel for IV infusion have been developed utilizing CREMOPHOR® EL (polyoxyl castor oil) as the drug carrier because of paclitaxel's aqueous insolubility. However, when administered intravenously, CREMOPHOR® EL is itself toxic and produces vasodilation, labored breathing, lethargy, hypotension and death in dogs. (Rowinsky et al, J. Natl. Cancer Inst. 82:1247-1259 (1990))
Docetaxel (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl paclitaxel) is commercially available as TAXOTERE® (Rhone-Poulenc Rorer) in a parenteral form. Docetaxel demonstrates a significant antitumour activity against various human malignancies, and is approved for treating patients with locally advanced or metastatic breast cancer, non-small-cell lung cancer, hormone refractory prostate cancer and advanced gastric cancer.
TAXOTERE® contains 40 mg/ml docetaxel and 1040 mg/ml polysorbate 80; it requires a first dilution with 13% ethanol before a further dilution in an intravenous infusion solution. Early in the clinical development of docetaxel, it became clear that docetaxel administration is associated with the occurrence of unpredictable (acute) hypersensitivity reactions. The occurrence of hypersensitivity reactions has, in part, been attributed to intrinsic toxic effects of polysorbate 80, and more specifically to oxidation products and oleic acid present in polysorbate 80, which are known to cause histamine release. (Lorenz et al, Agents Actions, 12: 64-80 (1982); Bergh et al, Contact Dermatitis, 37: 9-18 (1997)) Polysorbate 80 has been reported to increase plasma viscosity and produce changes in erythrocyte morphology; such effects have been suggested to contribute to mechanisms related to docetaxel-mediated cardiovascular side effects. (Mark et al, Br. J. Pharmacol, 134: 1207-1214 (2001))
Cabazitaxel is a taxane compound derived from the renewable needle biomass of yew plants. Cabazitaxel works by disrupting the microtubular network, which is essential for mitotic and interphase cellular functions and causes inhibition of cell division and cell death. Cabazitaxel has been shown to inhibit cell division and tumor cell proliferation by binding to and stabilizing tubulin, a protein in the microtubules of cells which provides a skeleton for maintaining cell shape.
Cabazitaxel is marketed as JEVTANA®, which is indicated in combination with prednisone for treating patients with hormone-refractory metastatic prostate cancer previously treated with docetaxel. JEVTANA® is supplied as a kit consisting of (a) a JEVTANA® injection, which contains 60 mg cabazitaxel in 1.5 mL polysorbate 80; and (b) a diluent, containing approximately 5.7 mL 13% (w/v) ethanol. Prior to administration, the JEVTANA® injection must first be mixed with the diluent, which dilutes the amount of cabazitaxel to 10 mg/mL, and then further diluted into a 250 mL PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion.
Docetaxel and paclitaxel with their broad anticancer activity, have contributed significantly to the improved treatment of a number of neoplastic diseases. Unfortunately, until now, the achievements obtained with these compounds have been mitigated by clinical limitations such as acquired or intrinsic resistance of tumors, poor CNS activity. Larotaxel is a semi-synthetic taxoid derivative, selected for development on the basis of its spectrum of in vitro and in vivo activity against taxane-resistant and multidrug-resistant tumors. Due to its broad spectrum of activity and with the possible advantages of surpassing some mechanisms of resistance and penetrating into the CNS, currently larotaxel is selected to conduct a clinical trial study.
Commercially available paclitaxel, docetaxel, and cabazitaxel drugs are administered via intravenous routes, requiring intervention by a physician or other health care professional, entailing considerable discomfort and potential local trauma to the patient and even requiring administration in a hospital setting. Many researchers are working on oral delivery of taxanes. However, paclitaxel and docetaxel were reported to have a poor or inconsistent oral bioavailability upon oral administration. To increase the bioavailability, some oral bioavailability-enhancing agent such as cyclosporin A, cyclosporin D, cyclosporin F or ketoconazole were co-administered to a mammalian patient. The enhancing agent was administered orally from 0.5-24 hours prior to the oral administration of one or more doses of the target agent, or substantially simultaneously with the target agent, or both prior to and substantially simultaneously with the target agent. However, this co-administration approach is not convenient for patients.
There exists a need for a method for delivering a taxane drug with improved bioavailability and fewer side effects.